Gene Expression Throughout Development of Pathology in APPKI Mice; Effects of Human Tau and Aging

2017, 2019

2019

Recent advances in technology have allowed the development of improved animal models for Alzheimer’s disease. This has required optimization of protein levels for the factors that influence progression of the disease, which has been done by replacing mouse proteins with humanized amyloid precursor protein that include disease-causing mutations and normal human tau. The amyloid precursor protein that contains mutations induces the early stages of Alzheimer’s disease. By adding normal human tau into the mice, this research will investigate how human tau influences disease progression. All effects will be evaluated in both male and female mice to help provide insights into why women are more prone to disease than men. The mice will be evaluated at early stages of disease progression to determine the influence of the plaques on the immune system and the activity of synapses. This project seeks to find molecular targets that could prevent the progression of Alzheimer’s disease at the early stages, as plaques develop, but before the symptoms of dementia begin.

2018

As the huge investments into cardiac and cancer research pay off with successful prevention and treatment of these common diseases, the average age of the world population continues to rise. This has the unfortunate consequence that age-related diseases, such as Alzheimer’s disease, are rising rapidly. The increased prevalence of Alzheimer’s disease in our aging population is becoming a crippling burden, both personally and financially for the families affected, and also for government health services across the world. This, the most urgent health problem of our time, must be solved. Understanding the underlying causes is the only way to develop effective treatments. Here we take advantage of recent improvements in animal models and technical advances in analysis of gene expression to achieve this goal, with the aim of finding new drug targets to tackle this ever-growing problem.

Alzheimer’s disease starts decades before the problem of brain deterioration becomes apparent. During
this time amyloid beta builds up in the brain and is increasingly deposited as amyloid plaques. But the disease only becomes problematic as further changes happen and tau tangles start to appear inside the brain cells. The most likely window of opportunity for preventing the loss of memory and other brain functions in Alzheimer’s disease is the long period when amyloid beta has started to rise as the plaque load increases but before tau tangles and brain degeneration set in. By the time Alzheimer’s disease is diagnosed, substantial loss of brain tissue already has occurred, particularly in the hippocampus, a structure important for memory. In this study, we concentrate on the effects on the hippocampus of rising amyloid beta beforeand during the increase of plaque load. Using new, improved mouse models expressing genes that cause

Alzheimer’s disease in humans, and taking advantage of recent technological advances, we will study the gene expression from the earliest stages, relating it directly to the first development of plaques and their progress throughout the life of the mice through to old age. In addition, we will investigate what is important about human compared with mouse tau, and assess whether itis critical for the final steps of the disease.

By comparing normal mice to mice with genes that cause different rates of rising amyloid beta, with and without human tau, we can work out which genes change their activity and how they are influenced by aging, giving us clues to which factors may be manipulated to prevent or delay disease progression. The data will be analyzed and published in the scientific literature, but it also will be added to a publicly available database that we have previously created for a study on dementia (www.mouseac.org). Anyone worldwide can look up any gene of interest and find out how it changes, and what other factors change with it, under these different conditions. This allows our data to benefit not only our research, but the research of scientists across the world, heading to a cure for Alzheimer’s disease.


Funding to Date

$394,374

Focus

Foundational Genetics, Genes to Therapies™ / Stem Cell Drug Screening

Researchers

Frances Edwards, Ph.D.


John Hardy, PH.D.